Diabetes最新文献

{"title":"Reducing PTP1B in the Hippocampus Protects Against Cognitive Decline in Prediabetes","authors":"Menglu Zhou, Xiaoying Yang, Xing Ge, Jiajia Chen, Wanyun Wu, Mingxuan Zheng, Xiaocheng Zhu, Xiaoying Cui, Renxian Tang, Kuiyang Zheng, Xu-Feng Huang, Libin Yao, Yinghua Yu","doi":"10.2337/db24-1167","DOIUrl":"https://doi.org/10.2337/db24-1167","url":null,"abstract":"The prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. Article Highlights The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenylosuccinate Mediates Imeglimin-Induced Proliferative and Antiapoptotic Effects in β-Cells","authors":"Ryota Inoue, Takahiro Tsuno, Takashi Nishimura, Setsuko Fukushima, Sayaka Hirai, Masayuki Shimoda, Yuto Yoshinari, Chisato Sakai, Tatsuya Kin, Euodia X. I. Hui Lim, Adrian Kee Keong Teo, Shinichi Matsumoto, A. M. James Shapiro, Jun Shirakawa","doi":"10.2337/db24-1090","DOIUrl":"https://doi.org/10.2337/db24-1090","url":null,"abstract":"Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. Article Highlights Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"22 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing Cerebral Microvascular Changes in Diabetic Rodents With Ultrasound Localization Microscopy","authors":"Xuan Ren, Gaobo Zhang, Boqian Zhou, Wenting Gu, Xue Jiang, Hongen Liao, Meng-Xing Tang, Xin Liu","doi":"10.2337/db25-0007","DOIUrl":"https://doi.org/10.2337/db25-0007","url":null,"abstract":"Microvasculature and hemodynamic changes in the cerebrovascular system are valuable indicators for the investigation of diabetic cerebrovascular disease. However, it is challenging for conventional imaging techniques to capture these minute features, meaning that the specific effects of diabetes on the brain vasculature and its potential disruption of brain function remain inadequately investigated. Ultrasound localization microscopy, with its unprecedented subdiffraction resolution and microvascular sensitivity, enables previously unobserved subtle variations to be revealed. Here, we aimed to leverage this advanced imaging technology to explore the alterations of brain in a diabetic rodent model in vivo. Parallel comparisons were made between diabetic rats and age-matched controls, and longitudinal assessments were performed before and after development of diabetes. In parallel comparisons, we found that rats with diabetes had significantly reduced vascular density in several key brain regions, including the striatum (13.70%), basal forebrain (8.48%), thalamus (12.20%), hypothalamus (20.85%), and hippocampus (8.73%). These findings were further supported by vascular staining and high-field MRI results. In addition, we demonstrated that a slowing of blood flow could be observed in the above brain regions. These results pave the way to understanding the effects of diabetes on the cerebral vasculature and may enable the future development of therapeutic and intervention strategies for diabetic cerebrovascular lesions. ARTICLE HIGHLIGHTS Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"153 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of Initial and Sustained Glycemic and Weight Response to Tirzepatide: A Post Hoc Analysis of SURPASS-4","authors":"Ewan R. Pearson, Stefano Del Prato, Imre Pavo, Denise R. Franco, Junyuan Zheng, Claudia Nicolay, Andrea Hemmingway, Russell J. Wiese, Steven E. Kahn","doi":"10.2337/db25-0276","DOIUrl":"https://doi.org/10.2337/db25-0276","url":null,"abstract":"This post hoc analysis assessed sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in people with type 2 diabetes and increased cardiovascular risk. Participants achieving HbA1c ≤48 mmol/mol (6.5%) or weight loss ≥10% at 52 weeks were evaluated for sustained glycemic or weight control and predictors of initial and sustained efficacy. For tirzepatide-treated participants achieving HbA1c ≤48 mmol/mol (6.5%) at 52 weeks, 75–84% sustained this until study end (median 81 weeks). Factors predicting achievement were higher tirzepatide dose, shorter diabetes duration, and lower HbA1c, higher HOMA of β-cell function (HOMA-B), metformin alone, and absence of albuminuria at baseline. Factors predicting sustained glycemic control were greater weight loss, smaller fasting glucose decrease, no sulfonylurea, and higher HOMA-B at 52 weeks. For participants achieving ≥10% weight loss at 52 weeks, 79–82% maintained weight loss. Factors predicting achievement were higher tirzepatide dose, female sex, no cardiovascular disease history, and lower baseline HbA1c, estimated glomerular filtration rate, and triglycerides. Greater decrease in LDL-cholesterol to 52 weeks predicted maintained weight loss. Greater weight loss and better β-cell function achieved with tirzepatide were the main predictors for sustained glycemic control in this post hoc analysis; no clinically meaningful predictor was identified for sustained weight control. Article Highlights We aimed to explore sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in a post hoc analysis. The question we wanted to answer was what predicted achieving and sustaining HbA1c and weight reduction in A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). We found greater weight loss and improved β-cell function were the main predictors for sustained glycemic control with tirzepatide therapy. No clinically relevant predictor was identified for sustained weight loss. Simple clinical measures may predict initial and sustained glycemic control and initial weight loss with tirzepatide.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained Weight Loss With Combined LEAP2 and Semaglutide Treatment in Mice","authors":"Stephanie K. Holm, Valdemar B. I. Johansen, Pablo Ranea-Robles, Charlotte Svendsen, Christoffer Merrild, Rebecca Rohlfs, Mauro Lo Conte, Wouter F. J. Hogendorf, Myrte Merkestein, Alexander N. Zaykov, Andreas M. Fritzen, Bharath K. Mani, Christoffer Clemmensen","doi":"10.2337/db24-1056","DOIUrl":"https://doi.org/10.2337/db24-1056","url":null,"abstract":"The recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor (GHSR) has revived interest in targeting the ghrelin-GHSR pathway for obesity treatment. Here, we assessed the preclinical efficacy of treatment with a long-acting LEAP2 (LA-LEAP2) analog for weight loss and explored its potential as an adjunct to semaglutide to enhance weight reduction and mitigate weight regain. We found that LA-LEAP2 lowered body weight in obese mice, which was reflected in reduced energy intake and preserved energy expenditure. While not uniformly observed across all experiments, some studies demonstrated superior weight reduction with the combination of LA-LEAP2 and semaglutide compared with semaglutide monotherapy. Notably, the combination also attenuated weight regain more effectively than semaglutide alone. Importantly, no signs of discomfort or behavioral aversion were detected following LA-LEAP2 administration. Collectively, these data indicate that LEAP2 analogs have the potential to enhance the efficacy of glucagon-like peptide 1 receptor agonism and support durable weight loss. ARTICLE HIGHLIGHTS Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous ghrelin receptor (GHSR) antagonist and inverse agonist, and represents a novel strategy to modulate the GHSR system for treatment of cardiometabolic disease. A long-acting LEAP2 (LA-LEAP2) analog induces significant weight reduction in rodent models without causing aversion. LA-LEAP2–mediated weight loss is driven by decreased energy intake alongside preservation of energy expenditure during weight loss. Combined LA-LEAP2 and semaglutide therapy supports durable weight loss, addressing a critical gap in obesity treatment.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"66 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fasting Lowers Glucagon Levels Under Basal Conditions and During Insulin-Induced Hypoglycemia in Individuals With Type 1 Diabetes","authors":"Nicole Sheanon, Shana O. Warner, Yufei Dai, Nat H. Whitsett, Shahriar Arbabi, Blair Hoeting, Shailendra B. Patel, Diana Lindquist, Jason J. Winnick","doi":"10.2337/db25-0251","DOIUrl":"https://doi.org/10.2337/db25-0251","url":null,"abstract":"Short-term fasting (<24 h) is common in individuals with type 1 diabetes (T1D), but it is associated with increased risk of hypoglycemia. Current strategies to mitigate this risk include changing the timing and/or dose of insulin; however, it is unclear whether counterregulatory hormone secretion is diminished, which would also contribute to this elevated risk. The current experiments were conducted to determine whether short-term fasting affects the hormonal and hepatic responses to insulin-induced hypoglycemia in those with T1D. Nine C-peptide–negative individuals with T1D gave their informed consent to participate in a randomly assigned crossover-design metabolic trial. In one study, participants ate an isocaloric breakfast and lunch before undergoing a hyperinsulinemic/hypoglycemic metabolic challenge in the evening (FED); in the other, they fasted before the hypoglycemic challenge (FAST). Immediately before insulin-induced hypoglycemia, glucagon concentrations were 43% lower in FAST compared with FED (31 ± 5 and 54 ± 6 pg/mL, respectively; P < 0.001), and endogenous glucose production (EGP) was 28% lower (3.4 ± 0.2 and 4.6 ± 0.3 mg/kg/min, respectively; P < 0.01). During insulin-induced hypoglycemia, the area under the curve for glucagon remained lower by 42% in FAST compared with FED (1,598 ± 229 and 2,768 ± 422 pg/mL ∗ 60 min, respectively; P < 0.01), as did EGP (41 ± 4 and 78 ± 12 mg/kg ∗ 60 min, respectively; P = 0.01). These data demonstrate that fasting lowers glucagon concentrations and EGP under euglycemic/normoinsulinemic metabolic conditions and during insulin-induced hypoglycemia. This reduction in metabolic flexibility, in addition to hyperinsulinemia, enhances susceptibility to fasting-induced low blood glucose in individuals with T1D and should be considered when developing strategies to avoid hypoglycemia. Article Highlights Fasting is associated with increased risk of hypoglycemia in patients with type 1 diabetes (T1D); however, little is known about how the counterregulatory responses to low blood sugar are affected under these metabolic conditions. During insulin-induced hypoglycemia, fasting (compared with eating normal meals for breakfast and lunch) glucagon concentrations were lower by 42% and endogenous glucose production by 47% in individuals with T1D. The secretion of other counterregulatory hormones during hypoglycemia was not affected by fasting (e.g., epinephrine, norepinephrine, cortisol). Fasting diminishes glucagon levels under hypoglycemic conditions in those with T1D, which may increase their susceptibility to hypoglycemia.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"635 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T-Cell Mediated Immunity to Gliadin Is Elicited in the Gut Mucosa of Type 1 Diabetes Patients Only in Presence of Celiac Disease Comorbidity","authors":"Carmen Gianfrani, Alessandra Camarca, Stefania Picascia, Serena Vitale, Ilaria Mottola, Martina Carpinelli, Mariantonia Maglio, Silvia Gregori, Adriana Franzese, Renata Auricchio, Riccardo Troncone","doi":"10.2337/db24-1120","DOIUrl":"https://doi.org/10.2337/db24-1120","url":null,"abstract":"Type 1 diabetes (T1D) and celiac disease (CeD) are two strongly associated autoimmune disorders, as they share genetic risk factors and immunopathogenic mechanisms. Several studies suggest an implication of gluten proteins, the causative antigen of CeD, in T1D pathogenesis. We investigated whether a gliadin-specific T-cell reactivity is present in the gut mucosa of children with T1D, with or without CeD comorbidity. Thirty-three young children were enrolled (median age 10 years) and divided in five groups based on T1D and/or CeD diagnosis. All patients underwent upper endoscopy for suspicion of CeD or gastrointestinal complaints, and duodenal biopsy specimens were processed for analysis of lymphoid cells phenotype and T cell–mediated reactiveness to gliadin. No substantial differences were found in the percentages of various T-cell subsets between the groups. No gliadin T-cell reactivity was found in T1D children negative for CeD, also in the presence of antibodies neutralizing regulatory cytokines interleukin 10 and transforming growth factor β. By contrast, a marked T-cell response to gliadin was detected in T1D with either potential (positive for CeD-associated autoantibodies and normal mucosa histology) or full-blown CeD (villous atrophy). In conclusion, no adaptive immunity to gluten occurs in the small intestine of T1D children in the absence of CeD comorbidity. Article Highlights It has been hypothesized that dietary proteins act as environmental factors in type 1 diabetes pathogenesis. This study investigated whether gliadin-specific T cells are present in the small intestine of children with type 1 diabetes, without or with celiac disease comorbidity. No sign of gliadin-reactive T cells, either proinflammatory or regulatory, was observed in the gut mucosa of children with type 1 diabetes negative for celiac disease autoimmunity. Interferon-γ producing T cells were detected in gut mucosa biopsy specimens of children with diabetes seropositive for antitissue transglutaminase antibodies. Our study does not support a pathogenic role of intestinal T cell–mediated immunity to gluten in type 1 diabetes pathogenesis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"292-OR: Oral Semaglutide and Cardiovascular Outcomes by Baseline A1C and BMI in People with Type 2 Diabetes in the SOUL Trial","authors":"SILVIO E. INZUCCHI, ROHANA ABDUL GHANI, JOHN DEANFIELD, MADS D.M. ENGELMANN, G. KEES HOVINGH, OLE K. JEPPESEN, MONIKA KELLERER, KABIRDEV MANDAVYA, JOHANNES F. MANN, NIKOLAUS MARX, CHANTAL MATHIEU, DARREN K. MCGUIRE, VISWANATHAN MOHAN, SHARON L. MULVAGH, RODICA POP-BUSUI, NEIL R. POULTER, MARIA SEJERSTEN RIPA, GABRIELA ROMAN, RÓBINSON SÁNCHEZ GARCÍA, MICHAEL SHECHTER, JOHN B. BUSE","doi":"10.2337/db25-292-or","DOIUrl":"https://doi.org/10.2337/db25-292-or","url":null,"abstract":"Introduction and Objective: In SOUL (NCT03914326), oral semaglutide (sema) 14 mg QD, a GLP-1 receptor agonist, reduced major adverse cardiovascular (CV) event (MACE) risk by 14%. GLP-1RAs are routinely prescribed to reduce A1c and BMI in type 2 diabetes (T2D). Whether the CV benefits of oral sema are influenced by baseline A1c or BMI is not fully known. Methods: SOUL’s primary outcome was time to first MACE, assessed for this post hoc analysis by baseline A1c, BMI and body weight using Cox regression. Results: People with T2D (n=9650; A1c 6.5–10%) and known atherosclerotic CV disease (ASCVD) or chronic kidney disease (CKD) were randomized to oral sema or placebo and followed for a mean of 47.5 months. We found significant differences in MACE outcomes associated with oral sema use by baseline A1c, with greater effects apparent with A1c >8.0% (Fig.). When the data were further analyzed across four A1c strata, the MACE benefit from oral sema appeared to apply to those with A1c >7%. The effects of oral sema on MACE were the same in those with BMI above / below 30 kg/m2, as well as across all four BMI strata, and above / below the mean body weight (87.9 kg) (Fig.). Conclusion: In SOUL, the CV benefits of oral sema appeared more pronounced with higher A1c levels at baseline but were consistent across various BMI categories. These data may help inform the individualized use of oral sema in people with T2D and ASCVD and/or CKD. Disclosure S.E. Inzucchi: Consultant; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc, Pfizer Inc, Bayer Pharmaceuticals, Inc. R. Abdul Ghani: None. J. Deanfield: Other Relationship; Aegerion Pharmaceuticals, Amgen Inc, AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Merck & Co., Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Novo Nordisk A/S, Pfizer Inc. M.D.M. Engelmann: Employee; Novo Nordisk. G. Hovingh: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. O.K. Jeppesen: None. M. Kellerer: Advisory Panel; Abbott, Bayer Pharmaceuticals, Inc. Speaker's Bureau; Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. K. Mandavya: Employee; Novo Nordisk. J.F. Mann: Other Relationship; AstraZeneca, Bayer Pharmaceuticals, Inc. Advisory Panel; Novo Nordisk. Board Member; AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Novo Nordisk. Other Relationship; Sanofi. Consultant; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk. Research Support; AstraZeneca. Other Relationship; Boehringer-Ingelheim. Research Support; Novo Nordisk, Sanofi. Speaker's Bureau; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk, Novartis AG. Other Relationship; UpToDate Inc / KDIGO. N. Marx: Speaker's Bureau; Abbott, Amgen Inc, AstraZeneca. Advisory Panel; AstraZeneca. Speaker's Bureau; Bayer Pharmaceutica","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"188 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subclasses of Glucose Trajectories in Early Childhood Stratified the Risk of Abnormal Glucose Tolerance in Adolescence and Young Adulthood","authors":"Yingchai Zhang, Eric S.H. Lau, Claudia H.T. Tam, Noel Y.H. Ng, Mai Shi, Atta Y.T. Tsang, Hanbin Wu, Aimin Yang, Hongjiang Wu, Lai Yuk Yuen, Elaine Y.K. Chow, Andrea O.Y. Luk, Alice P.S. Kong, Chi Chiu Wang, Juliana C.N. Chan, Wing Hung Tam, Ronald C.W. Ma","doi":"10.2337/db25-0256","DOIUrl":"https://doi.org/10.2337/db25-0256","url":null,"abstract":"Early-life exposures may shape long-term effects on glucose regulation. This study aimed to stratify long-term abnormal glucose tolerance (AGT) risk from early childhood. A total of 906 children were enrolled at baseline and reevaluated in adolescence and young adulthood. By using the latent class trajectory analysis, glucose trajectories of children were measured via five–time point oral glucose tolerance tests and then grouped into three latent subclasses: mild excursion–normal reversion (MN), moderate excursion–delayed reversion (MD), and severe excursion–delayed reversion (SD). Logistic regression was performed to estimate the risk of AGT and associations between cardiometabolic factors and subclasses. In adolescence, compared with the MN subclass, the risk of AGT was 1.7-fold in the MD subclass and 5.5-fold in the SD subclass, after adjusting for age, sex, BMI, and Tanner stage. In young adulthood, the adjusted risk of AGT was 3.6-fold and 11.6-fold in the MD and SD subclasses, respectively. During the full natural history of glucose tolerance, the risk of AGT was 3.6-fold in the MD subclass and 18.1-fold in the SD subclass, after adjusting for childhood covariates. MD and SD subclass membership was strongly associated with childhood hypertension, maternal gestational diabetes, and maternal hypertension during pregnancy. Glucose trajectory subclasses in early childhood effectively stratified the long-term risk of AGT. The association between maternal cardiometabolic health and childhood subclass membership highlighted that prenatal exposures may influence metabolic outcomes in offspring. Article Highlights Abnormal glucose tolerance (AGT) in youth has become an alarming global public health issue; however, approaches to identify high-risk population among young people have not been well-established. Can the long-term risk of AGT be stratified by the subclasses of glucose trajectories defined in childhood? Subclasses defined in childhood can efficiently stratify the risk of AGT in adolescence and young adulthood. The subclass membership was strongly associated with cardiometabolic disorders in childhood and maternal cardiometabolic disorders during pregnancy. This subclass method provides a potential strategy to identify those at risk of later cardiometabolic disorders from childhood for more intensive evaluation of intervention. The close relationship between maternal cardiometabolic disorders and subclass membership of children highlighted the potential influence of gestational cardiometabolic health on the development of cardiometabolic disorders in offspring.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage-Expressed Micropeptide Smim30 Maintains Adipose Tissue Insulin Sensitivity and Safeguards Systemic Metabolic Homeostasis","authors":"Yonghe Ma, Yu Shi, Kaiyuan Wu, Ping Li, Nikhil Gupta, Chengfei Jiang, Hang Sun, Xiangbo Ruan, Tyler Finley, Jing Wu, Chengyu Liu, Haiming Cao","doi":"10.2337/db24-0721","DOIUrl":"https://doi.org/10.2337/db24-0721","url":null,"abstract":"A growing number of micropeptides (miPs) have been identified in recent years, but their biological roles remain largely unexplored. We identified a conserved 6-kDa miP, named small integral membrane protein 30 (SMIM30), as a potential metabolic regulator. To study the physiological function of Smim30, we generated a loss-of-function mouse strain using the CRISPR/Cas9-mediated knock-in strategy. When fed both normal chow and high-fat diets, these mice exhibited elevated blood glucose and insulin levels, with reduced insulin sensitivity. We further showed that Smim30 loss in adipose tissue drove systemic insulin resistance, although intriguingly, adipocyte-expressed Smim30 was dispensable in this effect. Instead, Smim30 was mainly expressed in adipose tissue–residential macrophages, and loss of Smim30 led to increased macrophage infiltration and production of proinflammatory cytokines and chemokines. Smim30 also modulated inflammatory responses in ex vivo/in vitro macrophage systems, which are conserved in both humans and mice. The results indicate that Smim30 plays a key role in maintaining adipose tissue insulin sensitivity and safeguarding systemic metabolic homeostasis, offering potential as both a diagnostic biomarker and therapeutic target for metabolic disorders. Article Highlights Understanding the role of micropeptides (miPs) in metabolic regulation could enhance insights into metabolic diseases and open new pathways for treatment. Small integral membrane protein 30 (Smim30), an adipose tissue macrophage–expressed miP, maintains insulin sensitivity and safeguards systemic metabolic homeostasis. Smim30 modulates inflammatory responses and macrophage–adipocyte communication in adipose tissue. Smim30 could serve as a potential diagnostic biomarker and therapeutic target for metabolic disorders.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"57 74 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}